The contributions of genetic and environmental factors to the phenotypes of an organism are a perennial subject of the nature and nurture debate. It is now generally accepted that environmental factors are important in the determination of phenotypes by the genotypes, or nature through nurture. One of the best entry points to exploring the complex network of gene-environment interactions is through studies of neuronal and behavioral plasticity. Nervous systems are endowed with the capacity of self-modification in response to experience and external stimuli. Upon stress or injury by environmental challenges or system perturbations, neuro-protective and homeostatic mechanisms are evoked by intrinsic plasticity in neuronal and network functional organization. The specific aims of this proposal are: 1) To investigate extrinsic factors, including elevated environmental temperature and social deprivation, that influence neuronal growth and excitability as revealed by the striking phenotypes of Hk and Sh mutations affecting different K+ channel subunits. The cellular mechanisms in response to these stressors during development will be analyzed to demonstrate the underlying common features of the diverse forms of neural plasticity. 2) To study the intrinsic developmental regulation mechanisms that enable neuronal adjustment for recovering function upon mutational perturbations of ion channel function and membrane excitability. Striking plasticity in restoring synaptic stability is revealed by slo and Sh mutations, which provide opportunities to identify interacting genes in signal transduction pathways in the associated homeostatic processes. The results will provide unique opportunities to test three major hypotheses for the common threads linking different forms of neuronal plasticity: 1) Membrane excitability mechanism is a major player in neuronal homeostatic regulation in response to environmental stresses or genetic perturbations. 2) Metabolic stress as reflected by ROS accumulation triggers modifications of neuronal excitability and neural circuit function. 3) Activity-dependent Ca accumulation activates Ca/CaM-dependent adenylyl cyclase (encoded by rut) that plays a pivotal role in initiating different cascade events for modulation or synthesis of downstream effectors, such as ion channels, in homeostatic modifications. PUBLIC HEALTH RELEVANCE: The purpose of this study is to unravel the common threads linking different forms of neuronal and behavioral plasticity. We focus on mechanisms of homeostatic regulation of neuronal excitability and synaptic efficacy that enable adjustment and restoration of nervous system function upon environmental or mutational perturbations. The findings will have direct implications in the influence of environmental stress, social deprivation, and behavioral conditioning on mental and physical health.